tbuckley/cabot-search huggingface dataset:
Engineering of M2 Macrophages‐Derived Exosomes via Click Chemistry for Spinal Cord Injury Repair
Authors: Junkai Zeng, Changjiang Gu, Yanqing Sun, Xiongsheng Chen
Journal: Advanced Healthcare Materials (2023)

Abstract Spinal cord injury (SCI) is one of the most common causes of death and disability. The effective modulation of complicated microenvironment, regeneration of injured spinal cord tissue, and the functional recovery after SCI are still clinical challenges. Recently, macrophages‐derived exosomes have shown great potential for various diseases due to their inflammation‐targeting property. However, further modifications are needed to endow exosomes with the neural regenerative potential for SCI recovery. In the current study, a novel nanoagent (MEXI) is designed for SCI treatment by conjugating bioactive IKVAV peptides to the surface of M2 macrophages‐derived exosomes via an easy and rapid click chemistry method. In vitro, MEXI inhibits the inflammation by reprograming macrophages and promotes neuronal differentiation of neural stem cells. In vivo, engineered exosomes target the injured site of the spinal cord after tail vein injection. Furthermore, histological analysis reveals that MEXI improves motor functional recovery of SCI mice by reducing infiltration of macrophages, downregulating pro‐inflammatory factors, and improving the regeneration of injured nervous tissues. Taken together, this study provides strong evidence for the significance of MEXI in SCI recovery.
Effect of calcifediol supplementation as add-on therapy on the immune repertoire in recipients of the ChAdOx1 nCoV-19 vaccine: A prospective open-label, placebo-controlled, clinical trial
Authors: Swati Bhat, Liza Das, Deep Maheshwari, Darshan Badal, Roman Sarkar, Madhu Gupta, Surinder Singh Pandav, Bijaya Kumar Padhi, Sanjay Kumar Bhadada, Michael F. Holick, Pinaki Dutta, Naresh Sachdeva, Raman Kumar Marwaha
Journal: Journal of Infection (2023)
Severely ill COVID-19 patients have altered circulating levels of proteins controlling the epitranscriptome
Authors: A. Quiles-Jiménez, M.M.L. Sousa, C. Huse, A.M. Dyrhol-Riise, J.C. Holter, E.E. Christensen, K. Tonby, A.R. Holten, P. Aukrust, M. Bjørås, T.B. Dahl, B. Halvorsen
Journal: Journal of Infection (2023)
Natural killer cell memory precedes HLH in monozygotic twins discordant for chronic active Epstein-Barr virus disease
Authors: Chrissie K. Lim, Youjia Zhong, Richard Hopkins, Wei-Xiang Sin, Bijin Veonice Au, Sriram Narayanan, Chiung-Hui Huang, Colin YC Lee, Ming Liang Oon, Avisha Chowdhury, Benjamin Wong, Frances Yeap, Mariflor Villegas, Julien Pompon, Patricia PL Ng, Siok-Bian Ng, Thuan Chong T Quah, Poh-Lin Tan, Keh-Chuang Chin, John E Connolly
Journal: Blood (2023)

Severe mosquito bite allergy (SMBA) is a manifestation of chronic active Epstein-Barr virus (CAEBV) infection defined by necrotic ulceration of the stings. CAEBV with SMBA has a high mortality rate as most patients eventually develop fulminant and refractory hemophagocytic lymphohistiocytosis (HLH). However, how self-resolving SMBA escalates to systemic lethal HLH remains unclear. Through comprehensive immune profiling of a SMBA patient with CAEBV and her healthy monozygotic twin, we found that both twins were seropositive for EBV but showed high discordance in their circulating natural killer (NK) cells. The patient's EBV-infected NK cells displayed memory-like properties, including low CD16, high CD226 and induction of enhanced IFNγ production by IL-2 or IL-12. Her leukocytes also produced high levels of IL-2 and IL-12 when stimulated with salivary gland extract (SGE) specifically from A. albopictus mosquitoes, connected again with hyperproduction of IFNγ by her NK cells. Strikingly, pharmacological inhibition of STAT3 suppressed the NK memory-associated cytokine axis of IFNγ, IL-2 and IL-12 that is generated by A. albopictus SGE stimulation. Altogether, this study shows that NK memory is promoted during CAEBV with SMBA by repeated cytokine restimulation leading up to lethal HLH, and proposes STAT3 as a therapeutic target to halt its progression.
Emergence of epidemic variants of SARS-CoV-2 by acquiring combinations of new highly mutable nucleotides in its genome
Authors: Hui Wang, Yuqi Liu, Peng Li, Chaowu Liu, Kuibiao Li, Lan Cao, Ying Zhang, Zichun Cheng, Kailing Huang, Zhouxia Zheng, Xiaoqian Xin, Yifeng Liu, Xiaofang Peng, Dan Liang, Bixia Ke, Tao Wang, Qingpei Chen, Weihua Luo, Chaolang Qin, Lihong Sun, Guobing Chen, Oscar Junhong Luo, Jixi Li, Qiao Zhang, Biao Di, Zhoubin Zhang, Changwen Ke, Hongling Jia, Feng Gao
Journal: Journal of Infection (2023)
Next-generation sequencing analysis of hepatitis C virus resistance–associated substitutions in direct-acting antiviral failure in South Korea
Authors: Kyung-Ah Kim, Sejoon Lee, Hye Jung Park, Eun Sun Jang, Youn Jae Lee, Sung Bum Cho, Young Suk Kim, In Hee Kim, Byung Seok Lee, Woo Jin Chung, Sang Hoon Ahn, Seungtaek Kim, Sook Hyang Jeong
Journal: Clinical and Molecular Hepatology (2023)

We used next-generation sequencing (NGS) to analyze resistance-associated substitutions (RASs) and retreatment outcomes in patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment in South Korea. Using prospectively collected data from the Korean HCV cohort study, we recruited 36 patients who failed DAA treatment in 10 centers between 2007 and 2020; 29 blood samples were available from 24 patients. RASs were analyzed using NGS. RASs were analyzed for 13 patients with genotype 1b, 10 with genotype 2, and one with genotype 3a. The unsuccessful DAA regimens were daclatasvir+asunaprevir (n=11), sofosbuvir+ribavirin (n=9), ledipasvir/sofosbuvir (n=3), and glecaprevir/pibrentasvir (n=1). In the patients with genotype 1b, NS3, NS5A, and NS5B RASs were detected in eight, seven, and seven of 10 patients at baseline and in four, six, and two of six patients after DAA failure, respectively. Among the 10 patients with genotype 2, the only baseline RAS was NS3 Y56F, which was detected in one patient. NS5A F28C was detected after DAA failure in a patient with genotype 2 infection who was erroneously treated with daclatasvir+asunaprevir. After retreatment, 16 patients had a 100% sustained virological response rate. NS3 and NS5A RASs were commonly present at baseline, and there was an increasing trend of NS5A RASs after failed DAA treatment in genotype 1b. However, RASs were rarely present in patients with genotype 2 who were treated with sofosbuvir+ribavirin. Despite baseline or treatment-emergent RASs, retreatment with pan-genotypic DAA was highly successful in Korea, so we encourage active retreatment after unsuccessful DAA treatment.
Vitamin D influences gut microbiota and acetate production in zebrafish ( <i>Danio rerio</i> ) to promote intestinal immunity against invading pathogens
Authors: Xinmeng Liao, Yawen Lan, Wentao Wang, Jinjin Zhang, Rui Shao, Zhan Yin, Gudmundur H. Gudmundsson, Peter Bergman, Kangsen Mai, Qinghui Ai, Min Wan
Journal: Gut Microbes (2023)

Although evidence has shown that vitamin D (VD) influences gut homeostasis, limited knowledge is available how VD regulates intestinal immunity against bacterial infection. In the present study, cyp2r1 mutant zebrafish, lacking the capacity to metabolize VD, and zebrafish fed a diet devoid of VD, were utilized as VD-deficient animal models. Our results confirmed that the expression of antimicrobial peptides (AMPs) and IL-22 was restrained and the susceptibility to bacterial infection was increased in VD-deficient zebrafish. Furthermore, VD induced AMP expression in zebrafish intestine by activating IL-22 signaling, which was dependent on the microbiota. Further analysis uncovered that the abundance of the acetate-producer Cetobacterium in VD-deficient zebrafish was reduced compared to WT fish. Unexpectedly, VD promoted the growth and acetate production of Cetobacterium somerae under culture in vitro. Importantly, acetate treatment rescued the suppressed expression of β-defensins in VD-deficient zebrafish. Finally, neutrophils contributed to VD-induced AMP expression in zebrafish. In conclusion, our study elucidated that VD modulated gut microbiota composition and production of short-chain fatty acids (SCFAs) in zebrafish intestine, leading to enhanced immunity.
Short-Interval, Low-Dose [177Lu]Lu–Prostate-Specific Membrane Antigen in the Treatment of Refractory Glioblastoma
Authors: Stuart More, Thurandie Naiker, Nihaad Jacobs, Ferdinand Oompie, Vikas Prasad
Journal: Clinical Nuclear Medicine (2023)

Abstract Prostate-specific membrane antigen (PSMA) is expressed on the neovasculature as well as to some extent on the glioblastoma cells. With this background, we report the case of a 34-year-old man with recurrent glioblastoma who was treated with 2 cycles of low-dose [ 177 Lu]Lu-PSMA after exhausting all available treatment options in the state sector. Baseline imaging demonstrated intense PSMA signal in the known lesion, which was amenable to therapy. The prospect of [ 177 Lu]Lu-PSMA–based therapy for glioblastoma is warranted going forward.
Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice
Authors: Hamid Y. Dar, Daniel S. Perrien, Subhashis Pal, Andreea Stoica, Sasidhar Uppuganti, Jeffry S. Nyman, Rheinallt M. Jones, M. Neale Weitzmann, Roberto Pacifici
Journal: Journal of Clinical Investigation (2023)

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell-inducing taxon segmented filamentous bacteria (SFB), activation of γδ T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1-mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of γδ T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell-inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing.
B cell receptor ligation induces IgE plasma cell elimination
Authors: Adam K. Wade-Vallance, Zhiyong Yang, Jeremy B. Libang, Marcus J. Robinson, David M. Tarlinton, Christopher D.C. Allen
Journal: The Journal of Experimental Medicine (2023)

The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.
Dermatological caregiving: the need for a new paradigm
Authors: Carleen Walsh
Journal: British Journal of Dermatology (2023)

Journal Article Dermatological caregiving: the need for a new paradigm Get access Carleen Walsh Carleen Walsh Bamford Centre for Mental Health and Wellbeing, Ulster University, Coleraine, UK Correspondence: Carleen Walsh. Email: walsh-c33@ulster.ac.uk; Twitter: @CARLEENWALGAL Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 6, June 2023, Pages 797–798, https://doi.org/10.1093/bjd/ljad062 Published: 05 March 2023 Article history Received: 02 December 2022 Revision received: 31 January 2023 Accepted: 28 February 2023 Published: 05 March 2023 Corrected and typeset: 13 April 2023
FRC-derived retinoic acid: The key to unlocking milky spots
Authors: Alexander D. Daley, Cécile Bénézech
Journal: The Journal of Experimental Medicine (2023)

Milky spots of the omentum enable lymphocyte access to the peritoneal cavity. In this issue of JEM, Yoshihara and Okabe (2023. J. Exp. Med.https://doi.org/10.1084/jem.20221813) demonstrate how secretion of retinoic acid by fibroblastic reticular cells allows lymphocyte entry into milky spots and the peritoneal cavity.
Response to: Correspondence on "ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update" by Ramiro<i>et al</i>
Authors: Sofia Ramiro, Elena Nikiphorou, Alexandre Sepriano, Augusta Ortolan, Casper Webers, Xenofon Baraliakos, Robert BM Landewé, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2023)
The role of the sex hormone-gut microbiome axis in tumor immunotherapy
Authors: Luoyang Wang, Lei Tang, Dongchang Zhai, Meiying Song, Wei Li, Shuo Xu, Suli Jiang, Haining Meng, Jie Liang, Yingying Wang, Bei Zhang
Journal: Gut Microbes (2023)

Accumulating evidence suggested that both gut microbiome and sex play a critical role in the efficacy of immune checkpoint blockade therapy. Considering the reciprocal relationship between sex hormones and gut microbiome, the sex hormone-gut microbiome axis may participate in the regulation of the response to immune checkpoint inhibitors (ICIs). In this review, it was attempted to summarize the current knowledge about the influences of both sex and gut microbiome on the antitumor efficacy of ICIs and describe the interaction between sex hormones and gut microbiome. Accordingly, this review discussed the potential of enhancing the antitumor efficacy of ICIs through regulating the levels of sex hormones through manipulation of gut microbiome. Collectively, this review provided reliable evidence concerning the role of the sex hormone-gut microbiome axis in tumor immunotherapy.
Robust SARS-CoV-2 antibody and T cell immunity following three COVID-19 vaccine doses in inflammatory bowel disease patients receiving anti-TNF or alternative treatments
Authors: Eva Zhang, Thi H O Nguyen, Lilith F Allen, Lukasz Kedzierski, Louise C Rowntree, So Young Chang, Wuji Zhang, Jennifer R Habel, Isabelle J Foo, Tejas Menon, Jeni Mitchell, Rupert W Leong, Katherine Bond, Deborah A Williamson, Katherine Kedzierska, Britt Christensen
Journal: Gut (2023)
Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis
Authors: Shenghong Zhang, Baili Chen, Bangmao Wang, Hong Chen, Yan Li, Qian Cao, Jie Zhong, Ming-Jium Shieh, Zhihua Ran, Tongyu Tang, Ming Yang, Beibei Xu, Qiang Wang, Yunjie Liu, Lijia Ma, Xiaolin Wang, Nan Zhang, Su Zhang, Wenyu Guo, Liang Huang, Stefan Schreiber, Minhu Chen
Journal: JAMA (2023)

Importance Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. Objective To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Design, Setting, and Participants Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Interventions Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. Main Outcomes and Measures The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Results Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, −12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Conclusions and Relevance Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. Trial Registration ClinicalTrials.gov Identifier: NCT03235752
Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature
Authors: Lisa L Liu, Marcus Skribek, Ulrika Harmenberg, Marco Gerling
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions. Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation. We further provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase and the Web of Science Core Collection from inception to October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n=1866 articles, which were assessed for eligibility independently by two examiners. Of those, n=49 articles reporting on n=189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment were reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial under-reporting. The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.
Association of Stress With Cognitive Function Among Older Black and White US Adults
Authors: Ambar Kulshreshtha, Alvaro Alonso, Leslie A. McClure, Ihab Hajjar, Jennifer J. Manly, Suzanne Judd
Journal: JAMA Network Open (2023)

Perceived stress can have long-term physiological and psychological consequences and has shown to be a modifiable risk factor for Alzheimer disease and related dementias.
Sidestepping SHP2 inhibition
Authors: Bogdan Popescu, Kevin Shannon
Journal: The Journal of Experimental Medicine (2023)

Allosteric SHP2 inhibitors are a novel class of compounds that target hyperactive Ras/Mitogen Activated Protein Kinase (MAPK) signaling. In this issue of JEM, Wei et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20221563) report a genome-wide CRISPR/Cas9 knockout screen that uncovered novel mechanisms of adaptive resistance to pharmacologic inhibition of SHP2.